Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits.
Diabetologia
AIMS/HYPOTHESIS:Gestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits. METHODS:We collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Women's and Children's Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels. RESULTS:We identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p=4.42×10), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2 h OGTT glucose levels were 4 out of 4, 6 out of 9, 10 out of 11, 5 out of 7 and 4 out of 4, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM. CONCLUSIONS/INTERPRETATION:Our findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels. DATA AVAILABILITY:Summary statistics for GDM; fasting plasma glucose; 0 h, 1 h and 2h OGTT; and the 55 biomarkers are available in the GWAS Atlas (study accession no.: GVP000001, https://ngdc.cncb.ac.cn/gwas/browse/GVP000001) .
10.1007/s00125-023-06065-5
Myeloperoxidase G-463A and CYBA C242T genetic variants in gestational diabetes mellitus.
Endocrine connections
Oxidative stress plays an important role in the pathophysiology of gestational diabetes mellitus (GDM). We investigated the relationship between NADPH oxidase p22phox subunit (CYBA) C242T (rs4673) and myeloperoxidase (MPO) G-463A (rs2333227) genetic variants and GDM in 719 patients with GDM and 1205 control women. Clinical, metabolic, and oxidative stress parameters were analyzed. We found that frequencies of the A allele (15.6% vs 12.3%) and GA + AA genotype (28.5% vs 23.2%) of the MPO G-463A variation were significantly higher in patients with GDM than in the control women (OR = 1.318, 95% CI: 1.068-1.625, P = 0.010 for the dominant model; OR = 1.999, 95% CI: 1.040-3.843, P = 0.034 for the recessive model; OR = 1.320, 95% CI: 1.095-1.591, P = 0.004 for the allele model). Genotype GA + AA remained a significant predictor of GDM in a logistic regression model including age and BMI at delivery (OR = 1.282, 95% CI: 1.037‒1.583, P = 0.021). Furthermore, the ‒463A allele was associated with higher TG and the 242T allele was related to higher pre-pregnancy BMI and oxidative stress index in all subjects (P < 0.05). The 242T allele was also associated with higher homeostatic model assessment of insulin resistance but lower serum total antioxidant capacity in patients with GDM (P < 0.05). We conclude that the MPO G-463A, but not the CYBA C242T, genetic variation is associated with an increased risk of GDM in Chinese women. These two genetic polymorphisms may be linked to obesity, dyslipidemia, insulin resistance, and oxidative stress.
10.1530/EC-22-0369
Identification and Potential Clinical Utility of Common Genetic Variants in Gestational Diabetes among Chinese Pregnant Women.
Diabetes & metabolism journal
Background:The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods:We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results:Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion:Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.
10.4093/dmj.2024.0139
Genetic and inflammatory factors underlying gestational diabetes mellitus: a review.
Frontiers in endocrinology
Gestational diabetes mellitus (GDM) poses a significant global health concern, impacting both maternal and fetal well-being. Early detection and treatment are imperative to mitigate adverse outcomes during pregnancy. This review delves into the pivotal role of insulin function and the influence of genetic variants, including SLC30A8, CDKAL1, TCF7L2, IRS1, and GCK, in GDM development. These genetic variations affect beta-cell function and insulin activity in crucial tissues, such as muscle, disrupting glucose regulation during pregnancy. We propose a hypothesis that this variation may disrupt zinc transport, consequently impairing insulin production and secretion, thereby contributing to GDM onset. Furthermore, we discussed the involvement of inflammatory pathways, such as TNF-alpha and IL-6, in predisposing individuals to GDM. Genetic modulation of these pathways may exacerbate glucose metabolism dysregulation observed in GDM patients. We also discussed how GDM affects cardiovascular disease (CVD) through a direct correlation between pregnancy and cardiometabolic function, increasing atherosclerosis, decreased vascular function, dyslipidemia, and hypertension in women with GDM history. However, further research is imperative to unravel the intricate interplay between inflammatory pathways, genetics, and GDM. This understanding is pivotal for devising targeted gene therapies and pharmacological interventions to rectify genetic variations in SLC30A8, CDKAL1, TCF7L2, IRS1, GCK, and other pertinent genes. Ultimately, this review offers insights into the pathophysiological mechanisms of GDM, providing a foundation for developing strategies to mitigate its impact.
10.3389/fendo.2024.1399694
Serum CD44 levels in early pregnancy and its genetic variants for increased risk of gestational diabetes mellitus in Chinese pregnant women.
Journal of proteomics
This study aimed to explore associations of serum cluster of differentiation 44 (CD44) levels and its genetic variants in early pregnancy with gestational diabetes mellitus (GDM). We conducted a 1:1 case-control study (n = 414) nested in a prospective cohort of 22,302 pregnant women recruited from 2010 to 2012 in Tianjin, China. Blood samples were collected at the first antenatal care visit (at a median of 10 gestational week). Binary conditional logistic regressions were performed to examine associations of serum CD44 levels and its genetic variants with increased risk of GDM. In this study, we found that serum CD44 levels in early pregnancy was associated with GDM risk in a U-shaped manner. High serum CD44 levels and its genetic risk score in early pregnancy were associated with markedly increased risk of GDM after adjustment for traditional confounders (OR: 1.95, 95%CI: 1.12-3.40 & 1.95, 1.05-3.61). Furthermore, after adjustment for serum CD44 levels, the OR of CD44 genetic risk score for GDM was slightly attenuated but not significant (1.84, 0.98-3.48). In conclusion, serum CD44 levels and its genetic variants in early pregnancy were associated with GDM risk in Chinese pregnant women, with the effect of CD44 genetic variants being accounted for by serum CD44. SIGNIFICANCE: Recent studies suggested that pregnant women with GDM may have abnormal levels of CD44 and abnormal expression of CD44 gene, but it is uncertain whether abnormal CD44 plays a causal role in occurrence of GDM. Specifically, it remains unknown whether serum CD44 levels in early pregnancy and its genetic variants can predict the later occurrence of GDM. In this study, we found that high serum CD44 levels in early pregnancy and its genetic variants were associated with markedly increased risk of GDM in Chinese pregnant women, with the effect of CD44 genetic variants being largely accounted for by serum CD44 levels. Our study is the first reporting that serum CD44 levels and its genetic variants were associated with markedly increased risk of GDM. These multi-omics risk markers may be useful for identification of women at high risk of GDM in early pregnancy. Our findings also provide new insights into the disease mechanisms.
10.1016/j.jprot.2024.105268
Meta-analysis of the association between four CAPN10 gene variants and gestational diabetes mellitus.
Cui Junhao,Xu Xin,Yin Shuqing,Chen Fang,Li Peng,Song Chunlan
Archives of gynecology and obstetrics
PURPOSE:The purpose of the meta-analysis is to evaluate the association between calpain-10 (CANP10) gene polymorphisms and gestational diabetes mellitus (GDM). METHODS:A computer-based retrieval was performed in Web of Science, Embase and PubMed databases for eligible studies. The genotype data from four variants in CANP10 [single-nucleotide polymorphisms (SNP) 19, 43, 44, and 63] were collected. The pooled Odds ratios (ORs) with 95 % confidence intervals (CI) were conducted for five genetic models. RESULTS:Five studies containing 1003 GDMs and 1788 controls are included in this meta-analysis. The overall combined odds ratios show that SNP 19 and SNP 43 are not associated with increased risk of GDM in all genetic models. The association between SNP 63 and GDM is only significant in the heterozygous model (OR 2.79, 95 % CI 1.15-6.74). The SNP 44 is associated with increased risk of GDM in the recessive model (OR 1.75, 95 % CI 1.07-2.85), but only two studies are included. CONCLUSIONS:This meta-analysis indicates that women carriage of TT genotype in SNP 63 (rs5030952) is associated with increased risk in GDM.
10.1007/s00404-016-4140-8
Association of vascular endothelial growth factor expression and polymorphisms with the risk of gestational diabetes mellitus.
Dong Ping-Ping
Journal of clinical laboratory analysis
OBJECTIVE:To study the associations of vascular endothelial growth factor (VEGF) expression and its gene polymorphisms with the risk of gestational diabetes mellitus (GDM). METHODS:A total of 239 GDM patients (GDM group) and 275 healthy pregnant women (Control group) were included in this study. VEGF genotypes (including rs2146323, rs2010963, rs3025039, rs3025010, and rs833069) were analyzed by TaqMan assay. ELISA was used to determine the serum VEGF levels. The software SHEsis was performed to analyze haplotypes. RESULTS:The carrier with the rs2146323 AA, CA+AA genotypes, and A allele, as well as the rs3025039 CT, TT, CT+TT genotypes, and T allele showed the increased risk of GDM (all P < 0.05), but the distributions of genotype and allele at rs2010963, rs3025010, and rs833069 were not significantly different between GDM patients and controls (all P > 0.05). Notably, the frequency of rs2010963-rs833069-rs2146323-rs3025010 haplotypes CAAC, CAAT, CACC, CACT, GACT, and GGCT was found statistically different between GDM patients and controls (all P < 0.05). The patients with rs3025039 CT+TT genotype had higher VEGF levels than those with CC genotype (all P < 0.05). Besides, age, family histories of diabetes, previous GDM, hypertension, pre-pregnancy body mass index, fasting plasma glucose, fasting insulin, homeostasis model assessment (HOMA)-IR, rs2146323 CA+AA, rs3025039 CT+TT, and VEGF expression level were independent risk factors, while HOMA-β was an independent protective factor for GDM (all P < 0.05). CONCLUSION:VEGF rs2146323 and rs3025039 polymorphisms and its expression were significantly correlated with the risk of GDM, providing a great clinical value for GDM assessment and diagnosis.
10.1002/jcla.22686
Genetic variation of rs3811463 is associated with gestational diabetes mellitus susceptibility.
Liu Yun,Ge Zhi-Ping,Sun Li-Zhou,Tong Pei,Lu Hong-Mei
Experimental and therapeutic medicine
Gestational diabetes mellitus (GDM) is a growing health concern, and it increases the risk of adverse pregnancy outcomes with substantial long-term adverse health impacts on mothers and their offspring. Several studies have revealed specific associations between genetic variants and the risk of GDM. Single nucleotide polymorphisms (SNPs) are the major type of genetic variation in humans. Let-7 microRNA targets are enriched for genes containing SNPs associated with glucose metabolism, including Lin28. In the present study, the effect of T/C variants of rs3811463 (a SNP located near to the let-7 binding site in Lin28) on GDM risk was investigated. A GDM rat model was successfully constructed using a high fat diet and streptozotocin injection, and the primary skeletal muscle cells were isolated. The cell transfection results demonstrated that rs3811463-T/C significantly affected the glucose uptake and insulin sensitivity. Reverse transcription-quantitative polymerase chain reaction analysis indicated that the C allele at rs3811463 regulated the expression of glucose metabolism-associated genes insulin-like growth factor two binding protein 2 and glucokinase. Western blot analysis data revealed that replacement of the T allele by the C allele at rs3811463 modulated the protein level of Sirtuin 1. Taken together, it was concluded that the let-7/Lin28 axis regulated glucose uptake and insulin sensitivity by modulating the expression of glucose metabolism-associated proteins. These findings provide novel evidence on the association between genetic variations of rs3811463 and GDM susceptibility.
10.3892/etm.2017.5188
Association of vitamin D receptor gene polymorphisms with gestational diabetes mellitus-a case control study in Wuhan, China.
Liu Jianqiong,Dai Qiong,Li Wei,Guo Yan,Dai Anna,Wang Yanqing,Deng Mengyao,Tang Zhao,She Lu,Chen Xiaohong,Yang Mei
BMC pregnancy and childbirth
BACKGROUND:Gestational diabetes mellitus (GDM) increased risk of perinatal complications for both the women and the fetuses. The association between the vitamin D receptor (VDR) gene polymorphism and GDM has not been thoroughly investigated in Chinese pregnant women. Therefore, we aimed to determine whether VDR gene single nucleotide polymorphisms (SNPs) rs154410, rs7975232, rs731236, rs2228570 and rs739837 contribute to GDM risk in Wuhan, China. Moreover, we aimed to explore their combined effects on the risk of GDM. METHODS:Pregnant women who had prenatal examinations at 24 to 28 weeks' gestation in our hospital from January 15, 2018 to March 31, 2019 were included in this case-control study. After exclusion, a total of 1684 pregnant women (826 GDM patients and 858 non-diabetic controls) were recruited. The clinical information and blood samples were collected by trained interviewers and nurses. Genotyping of candidate SNPs was conducted on the Sequenom MassARRAY platform. Statistical analyses including t-test, ANOVA, chi-square test and logistic regression were performed to the data with SPSS Software to evaluate differences in genotype distribution and associations with GDM risk. Multifactor dimensionality reduction method was used to explore the gene-gene interactions on the risk of GDM. RESULTS:Differences in age, pre-pregnancy BMI, family history of diabetes and previous history of GDM between the case and control groups were statistically significant (P < 0.05), whereas no significant differences were found in height, gravidity, parity, and age of menarche (P > 0.05). There were no significant differences at genotype distributions of the examined VDR gene SNPs (P > 0.05). After adjusting by age, pre-pregnancy BMI, family history of diabetes, the results of logistic regression analysis showed no associations of the five SNPs with GDM in all the four genotype models(P > 0.05). Furthermore, there were no gene-gene interactions on the GDM risk among the five examined VDR gene SNPs. CONCLUSIONS:The VDR gene SNPs rs154410, rs7975232, rs731236, rs2228570 and rs739837 showed neither significant associations nor gene-gene interactions with GDM in Wuhan, China.
10.1186/s12884-021-03621-y
A Common R219K Variant of ATP-Binding Cassette Transporter A1 Gene Alters Atherometabolic Traits in Pregnant Women With Gestational Diabetes Mellitus.
Tang Fangmei,Guan Linbo,Liu Xinghui,Fan Ping,Zhou Mi,Wu Yujie,Liu Rui,Liu Yu,Liu Sixu,Li Dehua,Bai Huai
Frontiers in endocrinology
Background:ATP-binding cassette transporter A1 (ABCA1) has important roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport, and is implicated in lipid-related disorders. Genetic variants are involved in the pathogenesis of gestational diabetes mellitus (GDM). The objective of this study was to investigate the association of rs2230806 (R219K), a single nucleotide polymorphism (SNP) in the lipid-related gene, with the risk of GDM and related traits. Methods:The SNP, rs2230806, was genotyped, and clinical and metabolic parameters were determined in 660 GDM patients and 1,097 control subjects. Genetic associations with related traits were also analyzed. Results:The genotype distributions were similar in GDM patients and normal controls. However, significant differences in the variables examined in the study subjects were noted across the three genotypes. The genotype at the rs2230806 polymorphism was significantly associated with HDL-cholesterol (HDL-C) levels and atherogenic index (AI) values in GDM patients and total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels in control subjects. Subgroup analysis showed that the polymorphism was associated with diastolic blood pressure, in addition to HDL-C levels and AI, in overweight/obese GDM patients, while it was associated with TC levels, AI, pre-pregnancy body mass index (BMI), and BMI at delivery in non-obese GDM patients. In addition, this polymorphism was associated with TC, LDL-C, and apoB levels in overweight/obese control subjects. Conclusions:The rs2230806 polymorphism in the gene was associated with variations in atherometabolic traits in GDM patients, with characteristics of BMI dependency, but not with GDM. Our findings highlight a link between related phenotypes in women with GDM and genetic factors.
10.3389/fendo.2021.782453
Genetic variants of the GLP-1R gene affect the susceptibility and glucose metabolism of gestational diabetes mellitus: a two-center nested case‒control study.
Diabetology & metabolic syndrome
BACKGROUND:Gestational diabetes mellitus (GDM) is the most common complication during pregnancy, occurring under the combined action of environmental and genetic factors. Genetic variants of glucagon-like peptide-1 receptor (GLP-1R) have been reported to affect insulin secretion and susceptibility to type 2 diabetes. This study aimed to explore the role of GLP-1R polymorphisms in GDM and glucose metabolism. METHODS:A two-center nested case‒control study was designed, including 200 pregnant women with GDM and 200 pregnant women without GDM genotyped for five tag SNPs of GLP-1R using Sanger sequencing. Logistic regression was used to evaluate the relationship between GLP-1R polymorphisms and GDM risk. Glucose and insulin concentrations were measured based upon the 75 g oral glucose tolerance test (OGTT). Beta cell function of different genotypes was estimated with the 60 min insulinogenic index (IGI) and OGTT-derived disposition index (DI). RESULTS:Mutant genotype AG + GG of tag SNP rs6458093 nominally increased GDM risk (p = 0.049), especially among subjects younger than 35 years (p = 0.024) and with BMI no less than 24 (p = 0.041), after adjusting for confounders. Meanwhile, compared with subjects with wild genotype AA, subjects with genotype AG + GG of rs6458093 also showed nominally significantly lower IGI (p = 0.032) and DI (p = 0.029), as well as significantly higher 75 g OGTT-based 1 h glucose load plasma glucose levels (p = 0.045). Moreover, the mutant heterozygous genotype GA of tag SNP rs3765467 nominally decreased GDM risk among subjects older than 35 years (p = 0.037) but showed no association with insulin secretion and glucose homeostasis. CONCLUSIONS:Tag SNP rs6458093 of GLP-1R was nominally associated with increased GDM risk and affected beta cell function and postprandial glucose metabolism, while tag SNP rs3765467 of GLP-1R was nominally associated with decreased GDM risk, providing evidence for molecular markers and etiological study of GDM.
10.1186/s13098-022-00963-1
An association study between MiR-146a and INSR gene polymorphisms and hypertensive disorders of pregnancy in Northeastern Han Chinese population.
Lu Rui,Liu Nana,Feng Xiu,Feng Yanan,Zhang Shuang,Wu Yingnan,Jia Tianshuang,Yang Xuan,Lee Leo Tsz On,Sun Litao
Placenta
INTRODUCTION:Hypertensive disorders of pregnancy(HDP) is a complex and challenging group of pregnancy complications that is one of the leading causes of maternal and fetal death worldwide. Recent studies have shown that the single nucleotide polymorphism(SNP) may play a role in the pathogenesis of HDP. This study aimed to investigate the association of MiR-146a rs2910164 and insulin receptor(INSR) rs2059806 SNPs with HDP and their associated complications in the Han population of Northeast China. METHODS:A total of 240 HDP patients and 380 healthy controls were selected for genotype determination. For the most special and high incidence of HDP, we also studied the SNPs in association with pre-eclampsia(PE) patients. In addition, HDP complicated with gestational diabetes mellitus(GDM) patients was further analyzed to identify the association between SNPs and HDP-related complications. Multivariate logical regression analysis combined with 10, 000 permutation test corrections was used to analyze the association of MiR-146a and INSR SNPs with HDP. RESULTS:After adjusting for relevant factors, MiR-146a rs2910164 or INSR rs2059806 SNPs were not significantly different between HDP or PE patients and healthy controls(P>0.05). Meanwhile, MiR146a rs2910164 and INSR rs2059806 SNPs were not significantly different between HDP complicated with GDM and control group. DISCUSSION:Our data indicates that MiR-146a rs2910164 and INSR rs2059806 SNPs may not be significantly related with HDP in the Han population of Northeast China living in Heilongjiang Province.
10.1016/j.placenta.2020.11.011
Functional genetic variants in the 3'UTR of PTPRD associated with the risk of gestational diabetes mellitus.
Kang Yan,Huang Huamin,Li Haipeng,Sun Wenping,Zhang Cuicui
Experimental and therapeutic medicine
A previous study revealed that protein tyrosine phosphatase receptor type D (PTPRD) is highly associated with diabetes mellitus, particularly for type 2 diabetes, through a genome-wide association study. However, the influence of the human polymorphism in the 3'-untranslated region (3'-UTR) of PTPRD on gestational diabetes mellitus (GDM) has remained to be defined. The present study focused on the functional polymorphism located in the 3'-UTR of PTPRD and whether it is associated with the susceptibility to develop GDM. A total of 1,100 pregnant female patients aged between 28 and 36 years within gestational weeks 24-28 were recruited. The participants enrolled in the study comprised 500 cases of GDM and 600 normal controls. Based on the screening results, the single nucleotide polymorphism (SNP) rs56407701 exhibited the most significant difference and may increase the susceptibility to GDM. A prediction of target microRNAs (miRNAs/miRs) using the miRNA SNP database indicated that SNP rs56407701 may be bound by miR-450a, causing the suppression of PTPRD expression in subjects with the GC or CC genotype. In conclusion, The CC genotype of PTPRD rs56407701, which may be bound by miR-450a, may increase the susceptibility of Chinese Han females to GDM during pregnancy. The present study provided a theoretical basis for the SNP rs56407701 being a source of GDM susceptibility loci.
10.3892/etm.2021.9994
Novel association between a transient receptor potential cation channel subfamily M member 5 expression quantitative trait locus rs35197079 and decreased susceptibility of gestational diabetes mellitus in a Chinese population.
Journal of diabetes investigation
AIMS/INTRODUCTION:Emerging evidence suggests that expression quantitative trait loci (eQTLs) are more likely to associate with complex diseases. Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a ubiquitously expressed voltage-gated cation channel that acts indispensably to trigger insulin secretion in pancreatic β-cells. The present study evaluated the association between TRPM5 eQTL single-nucleotide polymorphisms and the risk of gestational diabetes mellitus (GDM) in a Chinese population. MATERIALS AND METHODS:A total of 380 unrelated Chinese pregnant women including 241 GDM patients and 139 controls were included in this study. The eQTL single-nucleotide polymorphisms of TRPM5 were obtained from the GTEx eQTL Browser, and were subsequently genotyped using the Agena MassARRAY iPLEX platform. RESULTS:Logistic regression analysis and linear regression analysis showed that rs35197079 and rs74848824 were significantly associated with reduced GDM risk and lower fasting plasma glucose levels after adjusting confounder factors in dominant genetic models. Stratification analysis based on pre-pregnancy body mass index validated a strong association between rs35197079 and GDM susceptibility in underweight and normal weight individuals. Luciferase and electrophoretic mobility shift assays carried out in rat pancreatic β-cells showed that rs35197079 was functional. CONCLUSIONS:The TRPM5 eQTL single-nucleotide polymorphism rs35197079 was associated with decreased GDM susceptibility in a Chinese population, especially in underweight and normal weight pregnant women, and it was functional in modulating gene transcription.
10.1111/jdi.13572
Association of polymorphisms in STRA6 gene with gestational diabetes mellitus in a Chinese Han population.
Medicine
Cell and animal experiments have found that in addition to being a retinol transporter, Stimulated by Retinoic Acid 6 (STRA6) also functions as a surface signaling receptor by which retinol regulates insulin responses. Several studies revealed that the STRA6 gene may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Gestational diabetes mellitus (GDM) and T2DM have some risk factors in common. The present study was directed to investigate whether the 3 single nucleotide polymorphism (SNPs) (rs11633768, rs351219, and rs736118) of STRA6 correlate with the development of GDM in Chinese pregnant women. We also aimed to estimate the relationship between SNPs with fasting blood glucose level, 1-hour and 2-hour blood glucose levels after 75 g oral glucose intake, fasting insulin and insulin resistance levels to better study the relationship between STRA6 and glucose metabolism.Case-control studies were conducted to compare the GDM and control groups. A total of 334 cases and 367 controls were recruited. Three tagSNPs of STRA6, rs11633768, rs351219, and rs736118, were selected. A chi-square test, logistic regression, and linear regression were used to estimate the relationship between SNPs with GDM risk and oral glucose tolerance test (OGTT), fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels. Regression analyses were all adjusted by maternal age, pre-pregnancy BMI, and weekly BMI growth. The Bonferroni correction was applied for multiple comparisons.After adjusting the maternal age, pre-pregnancy BMI and weekly BMI growth, STRA6 rs736118 was associated with fasting insulin level (Beta = -1.468, P = .036), and the association between rs736118 and HOMA-IR was of borderline significance (Beta = -0.290, P = .093) under the dominance model.This study found that there is a significant association between STRA6 polymorphism and GDM.
10.1097/MD.0000000000014885
Association of adiponectin gene polymorphism 45TG with gestational diabetes mellitus diagnosed on the new IADPSG criteria, plasma adiponectin levels and adverse pregnancy outcomes.
Han Yun,Zheng Yan-li,Fan Yu-ping,Liu Man-hua,Lu Xiao-yan,Tao Qian
Clinical and experimental medicine
The aim of this study was to identify the association of adiponectin gene single nucleotide polymorphism (SNP) 45TG with gestational diabetes mellitus (GDM) diagnosed on the new International Diabetes in Pregnancy Consensus Group (IADPSG) criteria, plasma adiponectin levels and adverse pregnancy outcomes in Han women of Nantong area in China. This cross-sectional study included 128 pregnant women with GDM (GDM group) and 140 pregnant women with normal glucose tolerance (NGT group) according to oral glucose tolerance test results based on the new IADPSG criteria. The GDM pregnant women were treated by diet control or diet control and insulin injection. All pregnant women attended antenatal cares and were recorded until delivery. Adiponectin gene was amplified through PCR, and SNP was detected using restriction enzyme SmaI. Plasma adiponectin levels were measured by ELISA. The G allele and TG+GG genotype were significantly more frequent than the T allele in the GDM group than in the NGT group (p < 0.05). Plasma adiponectin concentrations of TG+GG genotype carriers were significantly lower than those of TT genotype in both groups (p < 0.01). After adjustment for confounding factors, plasma adiponectin level remained significantly lower in pregnant women with TG+GG genotype than those with TT genotype (p < 0.05). Compared with the NGT group, the GDM group with glycemic control still had significantly higher incidences of macrosomia, neonatal hypoglycemia and asphyxia (p < 0.05). Further analysis revealed that the incidences of macrosomia and neonatal hypoglycemia were significantly higher in pregnant women with TG+GG genotype than those with TT genotype after adjustment for potential confounders in affecting pregnancy outcomes (p < 0.05). Even though pregnant women are diagnosed as GDM according to the new IADPSG criteria, the adiponectin SNP45 may be closely correlated with the prevalence of GDM in Han women of Nantong area in China, and the allele +45G in adiponectin gene might be associated with reduced plasma adiponectin levels and adverse pregnancy outcomes.
10.1007/s10238-014-0275-8
Association of CPT1A gene polymorphism with the risk of gestational diabetes mellitus: a case-control study.
Journal of assisted reproduction and genetics
PURPOSE:Gestational diabetes mellitus (GDM) is a growing public health problem worldwide and its etiology remains unclear. The pathophysiology of GDM is similar to that of type 2 diabetes (T2DM) and insulin resistance (IR) is the main reason for the development of GDM. Carnitine palmitoyltransferase 1A (CPT1A) is a candidate gene for metabolic disorders; however, the association of the CPT1A gene and GDM has not yet been studied. We aimed to explore whether single-nucleotide polymorphisms (SNPs) of the CPT1A gene could influence the risk of GDM. METHODS:We examined 18 single-nucleotide polymorphisms (SNPs) in the CPT1A gene and the risk of GDM in a nested case-control study of 334 GDM patients and 334 controls. The controls who had no GDM were randomly selected through matching to cases by age and residence. RESULTS:After adjusting the family history of diabetes, pre-pregnancy body mass index, and multiple comparison correction, the CPT1A rs2846194 and rs2602814 were associated with reduced GDM risk while rs59506005 was associated with elevated GDM risk. Moreover, the GGAC haplotype in the CPT1A gene (rs17399246 rs1016873 rs11228450 rs10896396) was associated with a reduced risk of GDM. CONCLUSION:Our study provides evidence for an association between genetic polymorphisms in the CPT1A and the risk of GDM.
10.1007/s10815-021-02143-y
Association between VDR genetic polymorphisms and risk of gestational diabetes mellitus in the Chinese population.
American journal of reproductive immunology (New York, N.Y. : 1989)
BACKGROUND AND AIMS:Abnormal metabolism of vitamin D was the primary mechanism in many pregnancy diseases. Our study was the first to examine the hypothesis that VDR gene polymorphisms contribute to the risk of gestational diabetes mellitus (GDM) in the Chinese population at high altitudes. MATERIALS AND METHODS:One hundred and eighteen women with GDM and 104 women with normal glucose tolerance (NGT) were included in this study using a case-control design. Four single nucleotide polymorphisms (g.47879112G > A, g.47846052C > T, g.47844974A > G, and g.47845054C > A) of mother and fetus were genotyped. RESULTS:Maternal and fetal frequency of the A allele of g.47879112G > A was significantly increased in women with GDM than in those with NGT (p < .05). A correlation between the AA homozygous genotype of g.47879112G > A and GDM was noted. Compared with non-carriers, A allele carriers showed higher fasting plasma insulin and two-hour post-challenge plasma glucose (2h-PPG), and lower levels of vitamin D. Furthermore, both maternal and fetal 4-marker haplotype ACCG were found to be significantly associated with GDM (p < .05). CONCLUSIONS:Association and haplotype analysis indicated that the A allele of g.47879112G > A could be a risk factor for GDM development in the Chinese population at high altitudes. Additionally, the VDR gene polymorphism of the fetus and mother may have a synergistic effect. The VDR polymorphism is associated with an increased risk of GDM and may be useful for predicting the development of the disease.
10.1111/aji.13778
Analysis of single nucleotide polymorphisms associated with the vitamin D pathway in the placentas of women with gestational diabetes mellitus: a laboratory study.
Journal of Yeungnam medical science
BACKGROUND:The aim of this study was to analyze the single nucleotide polymorphisms (SNPs) of genes known to be involved in vitamin D metabolism in the placenta using the placental tissue of mothers diagnosed with gestational diabetes mellitus (GDM) to determine whether the SNPs and occurrence of GDM are related. METHODS:We enrolled 80 women of the same gestational age, 40 with and 40 without GDM. The placenta was obtained from each woman after delivery and SNP genotyping was performed on seven SNPs in the CYP27B1 (rs10877012), CYP24A1 (rs2248359, rs6013897, and rs2209314), and GC (rs2282679, rs16847024, and rs3733359) genes. Maternal serum 25-hydroxyvitamin D levels were measured during the first trimester of pregnancy and before delivery. RESULTS:At the time of delivery, vitamin D levels were lower (21.05±12.05 mg/dL vs. 31.31±20.72 mg/dL, p=0.012) and the frequency of vitamin D deficiency was higher (60.7% vs. 32.5%, p=0.040) in the GDM group. In women with GDM, the G allele of rs10877012 was more common (86.3% vs. 65.0%, p=0.002). The rs10877012 GG genotype was more common in the GDM group (72.5% vs. 42.5%, p=0.007) and the rs10877012 TT genotype was more common in the control group (12.5% vs. 0%, p=0.007). CONCLUSION:Mothers with GDM have lower serum concentrations of vitamin D before delivery than healthy controls and vitamin D deficiency is common. A polymorphism in CYP27B1 (rs10877012), is considered to be a cause of GDM pathogenesis.
10.12701/jyms.2023.00150